Blood coagulation system consists of a cascade reaction which comprises numbers of combinations of various kinds of proteases and precursors (substrates) thereof, and is regulated mainly depending upon blood endothelial cells. When the blood endothelial cells are disordered to collapse cascade regulation of the blood coagulation, a thrombotic tendency is increased to lead to stenosis or occlusion of blood vessels. The thrombus consists of blood components coagulated intravascularly, which components include fibrin, platelet, erythrocyte, leukocyte and the like.
Fibrinolytic system is a rather simple system as compared with the blood coagulation system. However, factors related to the fibrinolytic system are deeply involved not only in an intravascular dissolution of thrombus but also in various reactions occurring in tissues, such as movement or migration of cell; ovulation; cell proliferation; angiogenesis; reconstruction (remodeling) of tissue; inflammatory response and the like. The fibrinolytic system is driven by serine proteases. The plasminogen is converted into plasmin by a plasminogen activator (hereinafter referred to as “PA”); a tissue-type plasminogen activator (hereinafter referred to as “tPA”); or a urokinase-type plasminogen activator (hereinafter referred to as “uPA”), and the resulting plasmin degrades a fibrin thrombus and tissue protein. The fibrinolytic reaction is regulated and modulated by a plasminogen activator inhibitor-1 (PAI1), a specific inhibitory protein against plasminogen activator existing in vivo. PAI-1 forms a complex with PA in a ratio of one to one to inhibit actions thereof. PAI-1 released from an activated platelet binds to fibrin so as to exist around the fibrin in a concentrated form, especially at the site of thrombogenesis, and inhibits an activity of tPA effectively. Furthermore, PAI-1 accelerates hyperplasia of vascular wall to promote progress of cardiovascular lesion by inhibiting degradation of extracellular matrix by a protease. An activity of the fibrinolytic system is regulated by a balance between PA and PAI-1. Therefore, an increase or a decrease of production of PAI-1 in cells or fluctuation in the activity of PAI-1 molecule is reflected immediately in the activity of the fibrinolytic system in blood. Accordingly, a therapeutic effect for thrombotic diseases is expected by inhibiting PAI-1 activity followed by promoting the activation of PA.
PAI-1 binds to vitronectin, which is a cell adhesion molecule, to inhibit adhesion of cells to the extracellular matrix. Therefore, a therapeutic effect for diseases caused by movement or migration of cell is also expected. Furthermore, plasmin which is indirectly activated by an inhibition of PAI-1 is involved in an activation of transforming growth factor as a cell proliferation inhibitory cytokine or in an activation of collagenase. Therefore, a therapeutic effect for diseases caused by cell proliferation, angiogenesis, and remodeling of tissue is also expected.
It has been reported that an expression of PAI-1 is increased at the lesion of arteriosclerosis to increase risks of thrombotic diseases such as myocardial infarction, deep vein thrombosis (DVT) and disseminated intravascular coagulation (DIC) associated with sepsis (see, Non-Patent Document 1), and a PAI-1 transgenic mouse shows a thrombogenic tendency (see, Non-Patent Document 2).
It has also been reported that a mouse model of obesity shows a significantly higher blood level of PAI-1, and further reported that PAI-1 is synthesized not only in endothelial tissues and hepatic tissues but also in adipose tissues, and an amount of synthesized PAI-1 is rapidly increased, especially in visceral fat (see, Non-Patent Document 3). Furthermore, it has been reported that a PAI-1 gene knock out mouse model of obesity shows a decrease in body weight, and a lowering of blood levels of glucose and insulin (see, Non-Patent Document 4), suggesting a possibility that PAI-1 aggravates various symptoms caused by an accumulation of fats. It has been reported that PAI-1 exists specifically in cancerous tissues to be involved in regulation of physiological function of cancer cells, and that a PAI-1 antibody inhibits metastasis of cancer in a cancer model (see, Non-Patent Document 5). It has also been reported that, when a transplantation of malignant keratinocytes into PAI-1 knock out mouse is carried out, invasion of cancer and angiogenesis are inhibited (see, Non-Patent Document 6).
Furthermore, it has been reported that PAI-1 is secreted from mast cell (see, Non-Patent Document 7), and an accumulation of extracellular matrix in an airway of a mouse model of asthma is alleviated by PAI-1 knockout (see, Non-Patent Document 8).
An arterial lesion as an acute or a chronic rejection after cardiac or renal transplantation is considered to be caused by progressions such as progression of fibrogenesis of tissue, progression of thrombogenesis, progression of proliferation and remodeling of arterial endothelial cell. In experiments of murine cardiac transplantation, when the compound having inhibitory action against PAI-1 was administered, take of a graft was significantly prolonged and an incidence of vascular intimal thickening was reduced to about one third as compared with control group (see, Patent Document 1). Accordingly, the compounds that can inhibit PAI-1 are considered to have inhibitory effects against acute rejections and arterial lesions after organ transplantation such as cardiac transplantation, renal transplantation or the like.
Therefore, compounds having specific inhibitory action against PAI-1 are expected to be agents useful for diseases caused by thrombogenesis, fibrogenesis, accumulation of visceral fat, cell proliferation, angiogenesis, deposition and remodeling of extracellular matrix, and cell movement and migration.
As for compounds having inhibitory action against PAI-1, the compounds disclosed in Patent Documents 1 to 19 and Non-Patent Documents 9 to 10 are known. However, the structural feature of the compounds of the present invention described below is clearly distinguishable from those of the compounds disclosed in the aforementioned documents.
As for {2-aralkyloxy-5-(aryl)phenyl}acetic acid derivatives, 2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-5-phenylphenyl]acetic acid is disclosed in Example 22 of Patent Document 20. However, no result of pharmacological test of the aforementioned compounds is disclosed in the aforementioned patent document. Furthermore, the aforementioned patent document fails to teach nor suggest that {2-aralkyloxy-5-(aryl)phenyl}acetic acid derivatives have inhibitory action against PAI-1.    Non-Patent Document 1: Proc. Natl. Acad. Sci. U.S.A., Vol. 89, No. 15, pp. 6998-7002 (1992).    Non-Patent Document 2: Nature, Vol. 346, No. 6279, pp. 74-76 (1990).    Non-Patent Document 3: Mol. Med., Vol. 2, No. 5, pp. 568-582 (1996).    Non-Patent Document 4: FASEB J., Vol. 15, No. 10, pp. 1840-1842 (2001).    Non-Patent Document 5: Gen. Diagn. Pathol., Vol. 141, No. 1, pp. 41-48 (1995).    Non-Patent Document 6: Nat. Med., Vol. 4, No. 8, pp. 923-928 (1998).    Non-Patent Document 7: J. Immunol., Vol. 165, No. 6, pp. 3154-3161 (2000).    Non-Patent Document 8: Biochem. Biophys. Res. Commun., Vol. 294, No. 5, pp. 1155-1160 (2002).    Non-Patent Document 9: Biochemistry, Vol. 37, No. 5, pp. 1227-1234 (1998).    Non-Patent Document 10: J. Med. Chem., vol. 47, No. 14, pp. 3491-3494 (2004).    Patent Document 1: European Patent Application Publication No. EP 1666469    Patent Document 2: The pamphlet of International Publication No. WO95/32190    Patent Document 3: The pamphlet of International Publication No. WO95/21832    Patent Document 4: U. K. Patent Application Publication No. GB 2372740    Patent Document 5: The pamphlet of International Publication No. WO03/000253    Patent Document 6: The pamphlet of International Publication No. WO03/000258    Patent Document 7: The pamphlet of International Publication No. WO03/000649    Patent Document 8: The pamphlet of International Publication No. WO03/000671    Patent Document 9: The pamphlet of International Publication No. WO03/000684    Patent Document 10: The pamphlet of International Publication No. WO2004/052856    Patent Document 11: The pamphlet of International Publication No. WO2004/052893    Patent Document 12: The pamphlet of International Publication No. WO2005/030192    Patent Document 13: The pamphlet of International Publication No. WO2005/030204    Patent Document 14: The pamphlet of International Publication No. WO2005/030715    Patent Document 15: The pamphlet of International Publication No. WO2005/030716    Patent Document 16: The pamphlet of International Publication No. WO2005/030756    Patent Document 17: U.S. Patent Application Publication No. US 2005/0124664    Patent Document 18: U.S. Patent Application Publication No. US 2005/0124667    Patent Document 19: U.S. Patent Application Publication No. US 2005/0143384    Patent Document 20: European Patent Publication No. EP 1357115